Pathophysiology and Management of Preeclampsia-Associated Severe Hyponatremia
Article Outline
Index Words: Hyponatremia, preeclampsia, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hypervolemic hyponatremia
Introduction
Severe hyponatremia is a rare complication of preeclampsia. Of 8 cases reported in the literature, the postulated mechanism was hypervolemic hyponatremia in 5 and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in the remaining 3. Irrespective of the type, early diagnosis and treatment are of the utmost importance. Hyponatremia in patients with preeclampsia may be associated with increased risk of maternal seizures, and fetal sodium level < 130 mEq/L (<130 mmol/L) can cause fetal jaundice, tachypnea, seizures, and polyhydramnios. Treatment of hyponatremia presents unique challenges in the setting of preeclampsia. Demeclocycline and conivaptan are contraindicated in pregnancy, and furosemide, a US Food and Drug Administration (FDA) class C drug, is best avoided. Fluid restriction alone may not always be effective, and worsening hyponatremia should be an indication for induction of labor. We report the fourth case of SIADH in patients with preeclampsia and discuss the pathophysiologic characteristics and management of severe hyponatremia in preeclampsia.
Case Report
Clinical History and Initial Laboratory Data
A 30-year-old nulliparous woman presented at 32 weeks of gestation with premature contractions. The patient had no significant medical history and the pregnancy to date had been uneventful. Physical examination showed blood pressure (BP) of 140/90 mm Hg in both arms (baseline, 100/70 mm Hg). Heart sounds were regular, and no murmur was heard. Lung examination findings were normal. Pedal edema was present. Laboratory tests showed the following values: serum sodium, 123 mEq/L (123 mmol/L; baseline, 135 mEq/L [135 mmol/L] at 28 weeks of gestation); potassium, 4.3 mEq/L (4.3 mmol/L; reference range, 3.5-5.1 mEq/L [3.5-5.1 mmol/L]); serum urea nitrogen, 9 mg/dL (3.2 mmol/L; reference range, 7-25 mg/dL [2.5-8.9 mmol/L]); serum creatinine, 0.6 mg/dL (53.0 μmol/L; reference range, 0.7-1.4 mg/dL [61.9-123.8 μmol/L); and estimated glomerular filtration rate, 125 mL/min/1.73 m2 (2.1 mL/s/1.73 m2). Liver function test results and serum uric acid level were normal. A sonogram of the fetus showed no distress. She underwent successful tocolysis with nifedipine and was admitted for observation by the obstetrics team. Subsequent BP readings were normal (average, 106/70 mm Hg), and 24-hour urine protein analysis was 500 mg (urine analysis at 28 weeks showed no protein). She had an uncomplicated 4-day stay in the hospital. Without intervention, serum sodium level was 126 mEq/L (126 mmol/L) at discharge.
At 33 weeks, the patient was readmitted for nephrotic-range proteinuria (protein, 5,049 mg/24 h). Physical examination showed BP of 108/70 mm Hg in both arms with significant pedal edema. Other physical findings were unchanged. Laboratory investigations showed serum sodium level of 125 mEq/L (125 mmol/L), with normal kidney and liver function test results. She was asymptomatic, and no fetal distress was noted. The patient was discharged from the hospital after 2 days with a serum sodium level of 124 mEq/L (124 mmol/L).
A third admission occurred at 34 weeks because of worsening proteinuria (protein, 5,990 mg/24 h). Physical examination findings were unchanged, and the patient was asymptomatic. BP was 100/70 mm Hg. No fetal distress was noted. Serum sodium level was 123 mEq/L (123 mmol/L), and the nephrology service was consulted for asymptomatic hyponatremia.
Additional Investigations
Additional laboratory tests showed urine osmolality of 325 mOsm/kg (325 mmol/kg) and serum osmolality of 266 mOsm/kg (266 mmol/kg). Urine sodium excretion was 77 mEq/L (77 mmol/L). Thyroid function test results and serum uric acid levels were normal. Morning serum cortisol levels were normal on 2 occasions (Table 1). She was placed on fluid restriction, with improvement in serum sodium level to 129 mEq/L (129 mmol/L) during the next 3 days. On day 4, she had a sudden decrease in sodium level to 123 mEq/L (123 mmol/L) associated with increased BP of 150/100 mm Hg.
Table 1. Routine and Additional Investigations at 34 Weeks of Gestation
| Parameter | Value |
|---|---|
| Serum | |
 Sodium (mEq/L) | 123 |
| Potassium (mEq/L) | 4.2 |
| Urea nitrogen (mg/dL) | 8 |
| Creatinine (mg/dL) | 0.5 |
| Albumin (g/dL) | 2.3 |
| Bilirubin, total (mg/dL) | <0.1 |
| Alkaline phosphatase (U/L) | 223 |
| Aspartate aminotransferase (U/L) | 18 |
| Alanine aminotransferase (U/L) | <3 |
| Lactate dehydrogenase (U/L) | 553 |
| Uric acid (mg/dL) | 4.3 |
| Cortisol, am (μg/dL) | 22 |
| Thyrotropin (mU/L) | 2.53 |
| Osmolality (mOsm/kg) | 276 |
| Hemoglobin (g/dL) | 9.7 |
| Platelets (×103/μL) | 202 |
| International normalized ratio (IU) | 0.9 |
| Fibrinogen (mg/dL) | 493 |
| Urine | |
| Osmolality (mOsm/kg) | 325 |
| Sodium, random (mEq/L) | 77 |
| Protein, 24-h total (mg/24 h) | 5,940 |
Diagnosis
SIADH in the setting of preeclampsia.
Clinical Follow-up
Although asymptomatic, the decision was made to induce labor. The patient received magnesium for seizure prophylaxis and oxytocin to augment labor. The delivery was uncomplicated.
In our patient, postpartum maternal sodium level increased to 135 mEq/L (135 mmol/L) within 48 hours, along with complete resolution of proteinuria, confirmed on 2 separate urine specimens. Neonatal sodium level was 128 mEq/L (128 mmol/L) at birth and improved to 137 mEq/L (137 mmol/L) within 48 hours. No oral salt supplement was required for the neonate. A summary of the approach is shown in Fig 1.
Figure 1.
Summary of the approach. All values shown are for serum sodium (in mEq/L). The patient was admitted first at 32 weeks and readmitted at 33 and 34 weeks of gestation. Nephrology was consulted in week 34, and fluid restriction was started. Labor was induced in week 35 due to worsening hyponatremia. Serum sodium level was 135 mEq/L within 48 hours postpartum. Serum sodium in mEq/L; no conversion necessary for expression in mmol/L. Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
Discussion
In general, hyponatremia can be classified as hypovolemic, euvolemic, or hypervolemic.1 In hypovolemic hyponatremia, nonosmotic release of antidiuretic hormone (ADH) secondary to volume depletion is associated with urinary sodium level usually < 10 mEq/L (<10 mmol/L). In patients with euvolemic hyponatremia, there is nonphysiologic release of ADH. This may be secondary to medications, lung or central nervous system disease, or tumors, most commonly small cell lung cancer. It also may be seen with glucocorticoid deficiency and hypothyroidism. Urinary sodium concentration usually is > 20 mEq/L (>20 mmol/L) in such cases. The third category is hypervolemic hyponatremia, commonly encountered in patients with heart failure, cirrhosis, or nephrotic syndrome. These patients have increased extracellular fluid volume with nonosmotic release of ADH from a low effective circulating volume. In these patients, urinary sodium concentration usually is < 10 mEq/L (<10 mmol/L) in the absence of diuretics.
Mild hyponatremia occurs most commonly in patients with normal pregnancy because of the phenomenon of reset osmostat.2, 3 It typically occurs in the first 2 months of pregnancy, and serum sodium levels usually are stable until delivery. The average decrease in serum sodium level is 5 mEq/L (5 mmol/L), and usually no intervention is required because the body defends plasma osmolality around the reduced set point. In our patient, the onset of hyponatremia at 32 weeks of gestation would be unusual for pregnancy-associated reset osmostat.
Severe hyponatremia is very rare in patients with preeclampsia, with only 8 cases previously reported (Table 2). In 5 of those patients, hyponatremia was classified as hypervolemic hyponatremia, and all except 1 patient had associated nephrotic-range proteinuria. Hayslett et al5 proposed that preeclampsia and nephrotic-range proteinuria together result in a low effective circulating volume. This in turn is believed to trigger nonosmotic release of ADH, similar to the mechanism seen in hyponatremia associated with heart failure and cirrhosis.5 Although this mechanism could have contributed to the development of hyponatremia in our patient, she also fulfilled diagnostic criteria for SIADH. A documented serum sodium level of 123 mEq/L (123 mmol/L) before the onset of nephrotic syndrome (on the day of the first admission) and urinary sodium excretion of 77 mEq/L (77 mmol/L) in the absence of diuretics suggest SIADH instead of hypervolemic hyponatremia. Three cases of SIADH in patients with preeclampsia have been reported previously. The exact mechanism of SIADH in the setting of preeclampsia is still in debate. Sutton et al8 proposed that a defective placenta in patients with preeclampsia does not produce sufficient vasopressinase, a placental enzyme that inactivates ADH. Another theory argues that premature contractions and preterm labor stimulate the placental unit and uterine myometrium to produce ADH and oxytocin under the influence of ovarian steroids.2 This release is pulsatile in nature, and the frequency of release increases with progression of labor. Alteration in the pulsatile nature or quantity of secretion of the 2 hormones could lead to hyponatremia.
Table 2. Summary of Reported Cases of Hyponatremia in Preeclampsia
aPostpartum. |
bMaternal level. |
Irrespective of the classification, hyponatremia presents unique challenges in the setting of preeclampsia. Hyponatremia may be associated with increased risk of seizures in patients with preeclampsia. Because fetal sodium rapidly equilibrates with maternal sodium, hyponatremia can develop quickly in the fetus. This can cause fetal jaundice, tachypnea, and seizures, especially if serum sodium level decreases to < 130 mEq/L (<130 mmol/L).5 Suppression of fetal ADH also can increase fetal urine output and may cause polyhydramnios.
Angiotensin-converting enzyme inhibitors are contraindicated for the treatment of nephrotic syndrome in pregnancy. In cases of SIADH in patients with preeclampsia, demeclocycline, a tetracycline derivative, is a class D drug, contraindicated in pregnancy. The vasopressin analogue conivaptan has not been studied in human pregnancies, and anecdotal evidence suggests decreased fetal viability and growth retardation. Furosemide is an FDA class C drug known to cause placental hypoperfusion and fetal electrolyte abnormalities.
In patients with preeclampsia-associated hyponatremia, in addition to BP control, fluid restriction and close monitoring of sodium levels should be instituted as part of the initial approach. Fluid restriction may be needed postpartum for up to 48 hours.8 For those not responding to fluid restriction alone, oral sodium chloride should be added and consideration should be given to early delivery of the fetus. Patients with worsening neurologic signs and symptoms may be started on 3% hypertonic saline immediately, with urgent delivery of the fetus.4, 5, 6, 7, 8
In conclusion, mild hyponatremia can occur in normal pregnancy, but severe hyponatremia is rare. Preeclampsia-associated hyponatremia may be severe. In those with SIADH and preeclampsia, demeclocycline and conivaptan are contraindicated, and furosemide is best avoided. In such patients, fluid restriction should be the initial approach, and oral salt supplementation should be initiated if unsuccessful. However, given the increased seizure risk for mother and fetus, worsening hyponatremia (with or without worsening preeclampsia) should be an indication for induction of labor because it is the only definitive treatment.
Acknowledgements
Support: None.
Financial Disclosure: None.
References
- . Hyponatremia. N Engl J Med. 2000;342(21):1581–1589
- . Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am J Physiol. 1984;246(1, pt 2):F105–F109
- . Involvement of oxytocin and vasopressin in the pathophysiology of preterm labor and primary dysmenorrhea. Prog Brain Res. 2002;139:359–365
- . Severe hyponatraemia and pre-eclampsia. Br J Obstet Gynaecol. 2004;111(9):1020–1022
- . Dilutional hyponatremia in preeclampsia. Am J Obstet Gynecol. 1998;179(5):1312–1316
- . Dilutional hyponatremia in preeclampsia with and without nephrotic syndrome. Am J Obstet Gynecol. 2001;184(2):231–232
- . Hyponatremia and preeclampsia. J Maternal Fetal Neonatal Med. 2005;18(1):77–78
- . Transient syndrome of inappropriate antidiuretic hormone secretion during pregnancy. Am J Kidney Dis. 1993;21(4):444–445
Originally published online as doi:10.1053/j.ajkd.2009.09.027 on December 11, 2009.
PII: S0272-6386(09)01313-4
doi:10.1053/j.ajkd.2009.09.027
© 2010 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
